Abnormal mineralization occurs in the context of several common conditions, including advanced age, diabetes, hypercholesterolemia, chronic renal failure and certain genetic conditions. Loss-of-function mutations in the ABCC6 gene cause chronic or acute forms of dystrophic mineralization in diseases such as Pseudoxanthoma elasticum (PXE) and dystrophic cardiac calcification (DCC). These pathologies are characterized by mineralization of cardiovascular and/or dermal tissues. PXE is heritable while DCC is an acquired phenotype resulting from cardiovascular insults. We have obtained preliminary data that suggest that ABCC6 initiates and modulates a calcification inhibitor pathway with a crucial role in both acute and chronic dystrophic calcification. We hypothesize that the loss of ABCC6 function in liver produces an imbalance of modulators of calcification in cardiovascular tissues either directly or through increased levels or modification of a circulating factor. To test this hypothesis, we will use a mouse models to characterize the effects of ABCC6 mutations on the structure and function of the protein, determine the response of Abcc6-/- mice to acute ischemic cardiac injuries and determine the role of Abcc6-/- in the calcification of the atherosclerotic plaque.
The overall goal of this proposal is to address the role of the ABCC6 gene in chronic and acute dystrophic calcification that affects cardiac and vascular tissues. To achieve the goals of this proposal, we will use mouse models to characterize the effects of ABCC6 mutations on the structure and function of the protein, determine the response of Abcc6-/- mice to acute cardiac ischemic injuries and determine the role of Abcc6 in the calcification of the atherosclerotic plaque.
|Pomozi, Viola; Brampton, Christopher; Szeri, Flóra et al. (2017) Functional Rescue of ABCC6 Deficiency by 4-Phenylbutyrate Therapy Reduces Dystrophic Calcification in Abcc6-/- Mice. J Invest Dermatol 137:595-602|
|Dedinszki, Dóra; Szeri, Flóra; Kozák, Eszter et al. (2017) Oral administration of pyrophosphate inhibits connective tissue calcification. EMBO Mol Med 9:1463-1470|
|Favre, Guillaume; Laurain, Audrey; Aranyi, Tamas et al. (2017) The ABCC6 Transporter: A New Player in Biomineralization. Int J Mol Sci 18:|
|Pomozi, Viola; Brampton, Christopher; van de Wetering, Koen et al. (2017) Pyrophosphate Supplementation Prevents Chronic and Acute Calcification in ABCC6-Deficient Mice. Am J Pathol 187:1258-1272|
|Leftheriotis, Georges; Kauffenstein, Gilles; Hamel, Jean François et al. (2014) The contribution of arterial calcification to peripheral arterial disease in pseudoxanthoma elasticum. PLoS One 9:e96003|
|Kauffenstein, Gilles; Pizard, A; Le Corre, Y et al. (2014) Disseminated arterial calcification and enhanced myogenic response are associated with abcc6 deficiency in a mouse model of pseudoxanthoma elasticum. Arterioscler Thromb Vasc Biol 34:1045-56|
|Brampton, Christopher; Aherrahrou, Zouhair; Chen, Li-Hsieh et al. (2014) The level of hepatic ABCC6 expression determines the severity of calcification after cardiac injury. Am J Pathol 184:159-70|
|Pomozi, Viola; Brampton, Christopher; Fülöp, Krisztina et al. (2014) Analysis of pseudoxanthoma elasticum-causing missense mutants of ABCC6 in vivo; pharmacological correction of the mislocalized proteins. J Invest Dermatol 134:946-953|
|Prunier, Fabrice; Terrien, Gwenola; Le Corre, Yannick et al. (2013) Pseudoxanthoma elasticum: cardiac findings in patients and Abcc6-deficient mouse model. PLoS One 8:e68700|
|Lefthériotis, Georges; Omarjee, Loukman; Le Saux, Olivier et al. (2013) The vascular phenotype in Pseudoxanthoma elasticum and related disorders: contribution of a genetic disease to the understanding of vascular calcification. Front Genet 4:4|
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